Tofisopam-Physical Properties/Chemistry
Tofisopam (structure shown below, with the atom numbering system indicated) demonstrates potent CNS modulating activity. Tofisopam is 1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine.

Tofisopam exists as a racemic mixture of (R)- and (S)-enantiomers. This is due to the asymmetric carbon (indicated by *) at the 5-position of the benzodiazepine ring. An asymmetric carbon is a carbon atom with four different groups attached.
The molecular structure and conformational properties of tofisopam have been determined by NMR, CD and X-ray crystallography. See, Visy et al., Chirality 1:271-275 (1989); the entire disclosure of which is incorporated herein by reference. In addition to existing as (R)- and (S)-enantiomers, each enantiomer of tofisopam exists in two stable conformations that may be assumed by the benzodiazepine ring as generally depicted below.

The sign of the optical rotation is reversed upon inversion of the diazepine ring from one conformer to the other. The major conformers, (R)-(+) and (S)-(−) have the 5-ethyl group in a quasi-equatorial position, while in the minor conformers, (R)-(−) and (S)-(+), the 5-ethyl group is positioned quasi-axially. Thus, racemic tofisopam can exist as four molecular species, i.e., two enantiomers, each of which exists in two conformations. In crystal form, tofisopam exists only as the major conformations, with dextrorotatory tofisopam being of the (R) absolute configuration. See, Toth et al., J. Heterocyclic Chem., 20:709-713 (1983); Bioorganic Heterocycles, Van der Plas, H. C., Ötvös, L, Simongi, M., eds. Budapest Amsterdam: Akademia; Kiado-Elsevier, 229:233 (1984); the entire disclosures of which are incorporated herein by reference.
The (R)- and (S)-enantiomers of tofisopam have been shown to possess different biological activity profiles. In particular, the use of the (R)-enantiomer of tofisopam, substantially free of the (S)-enantiomer of tofisopam, has been shown to be useful in the treatment of anxiety, resulting in diminished adverse effects and accordingly an improved therapeutic index as compared to administration of racemic tofisopam. See, U.S. Pat. No. 6,080,736, the entire disclosure of which is incorporated herein by reference.
Tofisopam—Synthetic Preparation of the Racemate
Racemic tofisopam is prepared by reacting 3,4,3′,4′-tetramethoxy-6-(α-aceto-propyl)benzophenone with hydrazine hydrate to form the corresponding hydrazone, 3,4,3′,4′-tetramethoxy-6-(1-ethyl-2-hydrazono-propyl)benzophenone. The hydrazone is then cyclized in the presence of methanol (MeOH) and gaseous hydrogen chloride to yield racemic tofisopam. See, U.S. Pat. Nos.3,736,315 and 6,080,736, the entire disclosure of which are incorporated herein by reference. The synthetic route to racemic tofisopam is depicted below:

The main impurities in the product resulting from the above reaction are the starting 3,4,3′,4′-tetramethoxy-6-(α-aceto-propyl)benzophenone and the hydrazone intermediate.
The resolution of tofisopam by chiral chromatography using macrocyclic glycopeptide as a stationary phase on a Chirobiotic V™ column (ASTEAC, Whippany, N.J.) and using 10% MeOH in tert-butylmethyl ether as the mobile phase, is disclosed in U.S. Pat. No. 6,080,736. In this method, the (R)-(+) enantiomer was the first compound to elute from the column. (R)-(−)-tofisopam, (S)-(−/+) tofisopam, and residual (R)-(+)-tofisopam co-eluted and were collected in a subsequent fraction. Fitos et al. (J. Chromatogr., 709 265 (1995)), discloses another method for resolving racemic tofisopam by chiral chromatography using a chiral α1-acid glycoprotein as a stationary phase on a CHIRAL-AGP™ column (ChromTech, Cheshire, UK), and 10% ACN in a pH 7.0 phosphate buffer as the mobile phase. Zsila et al., disclose another resolution of tofisopam using Chiralcel® OJ® (Daicel) as a stationary phase and n-hexane, 2-propanol and MeOH (72:1.5:3) as a mobile phase, in a method taking more than 40 minutes to elute the enantiomers.
None of the disclosed methods has been optimized for production of large quantities of (R)-tofisopam of a chemical and enantiomeric purity suitable for preparation of a drug formulation. What is needed is an industrially applicable procedure for isolation of (R)-tofisopam, substantially free of the (S)-enantiomer of tofisopam, which:
(a) provides high chemical purity;
(b) provides high enantiomeric purity;
(c) provides high yield of the (R)-tofisopam; and
(d) provides the above features in an economically feasible process.